麻豆传媒

SAN DIEGO -- A novel drug significantly reduced IgA nephropathy-related proteinuria, according to interim findings of the ALIGN study.

In the phase III trial, among 270 patients with the rare kidney disorder, those on atrasentan had a 36.1 percentage point (95% CI -44.6 to -26.4, P<0.001) greater reduction in urinary protein-to-creatinine ratio (UPCR) relative to baseline than placebo, reported Hiddo J.L. Heerspink, PhD, of the University Medical Center Groningen in the Netherlands, at the American Society of Nephrology Kidney Week meeting.

Over the course of 36 weeks, patients on 0.75 mg/day of atrasentan had a 38.1% reduction in UPCR versus a 3.1% reduction with placebo. The on-treatment group had a significant UPCR reduction by week 6.

"This benefit is clinically meaningful, especially in the context of a high-risk trial population (patients had a total urinary protein excretion of ≥1 g per day at baseline, despite appropriate supportive care)," Heerspink and colleagues stated in a paper that was simultaneously published in the (NEJM).

"Although the final results of the ALIGN trial will be needed to confirm that the proteinuria reduction seen with atrasentan translates to a reduction in eGFR decline, there is growing confidence in the urinary protein-to-creatinine ratio as a surrogate biomarker in IgA nephropathy," they said.

Heerspink said results for eGFR change from the main stratum will be presented after all patients have completed the 136-week double-blind study period. This endpoint will show if the drug truly preserves kidney function.

New therapies are needed for IgA nephropathy, as around half of patients will progress to kidney failure within 20 years of diagnosis. This unmet need has led to a recent push towards developing new therapies like atrasentan, which acts as a selective inhibitor of the endothelin type A receptor.

Other newly developed drugs for IgA nephropathy include targeted-release budesonide (Nefecon) and iptacopan (Fabhalta) -- an alternative complement pathway inhibitor -- which gained accelerated FDA approval in August 2024 based on positive interim trial findings that used the same surrogate endpoint of proteinuria reduction. This drug awaits traditional approval following anticipated eGFR trial results with the APPLAUSE-IgAN trial.

"Both of these trials [ALIGN and APPLAUSE-IgAN] are judged to be promising, given that trials with surrogate end points are widely considered to be predictive," Julie R. Ingelfinger, MD, NEJM deputy editor, said in an .

"Yet, whether and how often drugs already or soon-to-be approved on an accelerated pathway on the basis of such surrogate end points will have continued approval once results from planned hard end points are evaluated is not yet clear," she added. "Doubtless, results of those latter end points will influence the life of this new pathway."

Atrasentan previously demonstrated efficacy in the open-label AFFINITY basket trial, where it reduced the 24-hour urinary protein-to-creatinine ratio by 48% after 12 weeks of treatment when added to maximum tolerated doses of angiotensin-converting-enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs).

In the double-blind ALIGN study, 340 patients were recruited, but the interim results only reflect the first 270 patients in the main stratum (135 per trial group) who completed the week 36 visit.

Trial participation was exclusive to adults with biopsy-proven IgA nephropathy, a total urinary protein excretion of at least 1 g per day, and an eGFR of at least 30 mL/min/1.73 m2. All were on a maximum tolerated dose of an ACE inhibitor, or a stable dose of ARB, for at least 12 weeks before screening. Patients who were unable to take RAS inhibitors were eligible; however, the total percentage of such patients could not exceed 5% of the total population," the authors explained.

Average participant age was 45, 41% were female, 47% were from Asia, mean baseline eGFR was 58.9 mL/min/1.73 m², and median UPCR was 1,433 mg/g.

In a subgroup analysis which stratified patients based on gender, age, race, ethnicity, continent, and whether they were from Asia or not, nearly all groups favored atrasentan. The only two subgroups that had nonsignificant UPCR decline were six patients, ages 65 and older, and the 12 patients from Europe.

All subgroups stratified by clinical characteristics -- baseline and screening UPCR, blood pressure, eGFR, and diuretic use -- favored atrasentan.

Patients taking an SGLT2 inhibitor could be enrolled in an exploratory stratum. This subset of 29 patients had results similar to the main stratum, marked by a -39.6% UPCR reduction in 14 atrasentan patients and -3.4% (95% CI -26.3 to 26.5) in the 15 placebo patients at week 36 (geometric mean between-group difference of -37.4 percentage points, 95% CI -57.2 to -8.5).

Atrasentan was also well tolerated with a favorable safety profile, marked by a similar percentage of patients with adverse events (AEs) between the two groups. No serious treatment-emergent AEs or AEs leading to study drug discontinuation occurred.

Nasopharyngitis, peripheral edema, anemia, pyrexia, and upper respiratory tract infection were more common AEs in the atrasentan group than in the placebo group. Also, some AEs of special interest -- anemia, fluid retention, and vasodilatation or hypotension -- were more common with atrasentan.